The term “Orally disintegrating formulation” used herein refers to those that rapidly disintegrate or dissolve in oral cavity. Such a formulation disintegrates rapidly and mostly dissolves upon contacting with saliva, which formulation will be swallowed by a patient thereafter. Its taste is palatable and no gritty feeling is perceived. The orally disintegrating formulation emerged in late 1970s, when Gregory et. al prepared a drug carrier with high porosity by freeze-drying. The carrier could disintegrate upon contacting with saliva in oral cavity. The orally disintegrating formulation becomes more and more popular for its special advantages, such as being swallowed without the aid of water and rapid disintegration in oral cavity, which provides convenience to the patients who have swallow difficulty or have no easy access to water.
Currently, the orally disintegrating formulation has been developed overseas which is prepared by using hydrolyzed gelatin able to disintegrate rapidly in water as the matrix of drug (U.S. Pat. No. 4,305,502) and releases active ingredients rapidly in oral cavity. It is well known that the orally disintegrating formulation has a broad drug-loaded range and hydrolyzed gelatin is used as carrier or matrix-forming agent of drug in a lot of rapidly releasing formulations. Typically, the hydrolyzed gelatin is characterized in that it can enhance the hardness of the formulation and prevent the formulation from crashing when released from the package.
Gelatin mostly comes from hydrolyzed product of the animal collagen tissues, such as skin, tendon, ligament and bones. It is a common technique to apply hydrolyzed gelatin as a drug carrier and matrix-forming agent. But in recent years, the emerge of the animal origin diseases, such as mad cow disease, foot and month disease, scrapie and the like, results in more and more doubts as to the safety of hydrolyzed gelatin. Moreover, gelatin product obtained from pigs could't be acceptable by the Muslim people and people with other religions, and gelatin product obtained from animal is also unacceptable by vegetarians.
It is difficult to apply hydrolyzed gelatin as an excipient in the preparation process. Firstly, in order to sufficiently dissolve the hydrolyzed gelatin, it is necessary to heat the hydrolyzed gelatin, and the producing process using hydrolyzed gelatin as an excipient needs a heating-step. As a result, it not only prolongs the preparation period of orally disintegrating formulation, but also increases the cost. In the traditional process, it is necessary to keep the mixture containing hydrolyzed gelatin for a longer time to make the liquid system disperse homogeneously. But the viscosity of the mixture of hydrolyzed gelatin acting as an excipient increases with time, causing more difficulties to process. Moreover, in the sublimation-drying process, the hydrolyzed gelatin is inclined to forming a dense film on the surface of the formulation, which is not completely dried, thus preventing the moisture from further sublimating from the inner part of the formulation and drying. Therefore, the subsequent drying process becomes more complicate, which in turn increases the production cost. Furthermore, the elevation of the product temperature will destroy the unstable active ingredient.
Another problem encountered through using the hydrolyzed gelatin is the narrow scope of the active ingredient used in the formulation. Because hydrolyzed gelatin has some properties of protein and polypeptide, it is not suitable to use it in formulation containing an active ingredient which is apt to react with protein and polypeptide. Therefore, the utility of the hydrolyzed gelatin is limited when being used in the formulation of a compound drug with more phenol and hydroxyl groups, traditional Chinese medicine and its active ingredient, such as the soluble salvianolate, as well as other soluble ingredients containing tannins in traditional Chinese Medicine.
As a solution to the above problems, pullulan has been proposed abroad (WO 00/50013) to be used instead of hydrolyzed gelatin as the binder of the orally disintegrating formulation to produce orally disintegrating formulation. Although the solution overcomes the drawbacks of the orally disintegrating formulation using hydrolyzed gelatin as the binder, because a saccharide or alditol is used in the orally disintegrating formulation as the matrix-forming agent and has high hygroscopicity, the formulation is easy to absorb moisture of the air in the manufacturing process, which leads to partial or complete collapse of the matrix structure and a longer disintegrating time. Furthermore, the formulation shrinks due to the hygroscopicity and the appearance of formulation becomes grotty, which results in detest of the consumer in the vision. Even more severely, such a formulation is forbidden coming into the market for its quality is not in conformity with the Quality Standard. To solve this problem, a process was brought forward, i.e., the traditional orally disintegrating formulation is air tightly sealed using double aluminum packing materials, by which, the formulation is kept away from the moisture of the air. However, the process only provides a temporary solutions rather than a final solution. Not only is a great deal of aluminum material used, resulting in the resource waste, but also the cost of the formulation increases. Furthermore, even if using the aluminum package, a patient, when taking the formulation from the package, usually feels uncomfortable as the formulation adheres to the hands due to the high hygroscopicity. This takes place more usually in summer. Therefore, there is an urgent need for a new formulation which can overcome the defects brought by the using of the hydrolnyzed gelatin as a binder, at the same time, the hygroscopicity of which is lower as compared with the disintegrating formulation using saccharide or alditol as a matrix-forming agent, and the appearance and the disintegrating time of which is not affected by the moisture of the air.
Besides, if the active ingredient is a protein or a polypeptide drug, the structure of the active ingredient will be destroyed by the mechanical effects produced in the freezing process and its activity will be decreased.
In order to solve the above-mentioned problems, the inventors of the present invention has done extensive research and completed the invention.